SUMMARY/ABSTRACT The capacity for individuals to recover motor function after stroke or traumatic brain injury is thought to be largely dependent upon adaptive plasticity mechanisms in uninjured regions of the brain. Over the past 20+ years, investigators have demonstrated a remarkable array of neurophysiological and neuroanatomical changes after focal cortical injury in animal models, especially in spared cortical areas. Many of these changes have been correlated with functional motor recovery. Also, neuroimaging and noninvasive stimulation studies in human stroke survivors have shown changes in both the injured and the intact (or contralesional) hemisphere. However, a focus of continuing debate is whether contralesional plasticity is adaptive, maladaptive, or epiphenomenal. From a clinical perspective, this is a critical topic, since many investigators are now employing non-invasive stimulation techniques to modulate activity in the intact hemisphere after stroke to improve motor function. Our long-term goal is to provide a comprehensive understanding of the neural mechanisms underlying recovery of function after brain injury. The objective of this application is to assess the behavioral significance of post-injury neuronal plasticity, especially within the intact hemisphere. To this end, we will utilize our extensive experience in neurophysiological recording, neuroanatomical tract-tracing and behavioral approaches in mammalian models of injury and recovery to describe in detail the role of neuronal plasticity in recovery of motor skills. Our central hypothesis is that spared cortical motor areas in the injured and uninjured hemispheres play evolving and interdependent roles in the execution of motor tasks during functional recovery (Aim 1), and that the participation of the intact hemisphere is dependent upon task complexity (Aim 2), lesion anatomy (Aim 3), and post-injury behavioral experience (Aim 4). We also propose that post-injury plasticity is associated with altered interhemispheric neuroanatomical connections (Aim 5). With this new and unique information, investigators will be better able to design evidence-based interventions to help restore function after cortical injuries. The application of chronic microelectrode recording techniques to the question of neural network plasticity after cortical injury is quite novel. While motor output maps in anesthetized animals have revealed behaviorally-relevant changes after injury, neuronal activity patterns (task- related spike activity, local field potentials, interhemispheric communication) after injury in ambulatory animals is largely unknown. At the conclusion of the proposed five-year project, we expect to have contributed in a unique and substantial way to understanding cortical network dynamics after injury, significantly advancing our ability to design future therapeutic interventions based on a firm mechanistic footing.